Coronary atherosclerosis is the major cause of death in women in the United States. Coronary artery bypass surgery decreases symptomatic and clinical evidence of cardiac ischemia, but does not alter the underlying process. Patients may develop recurrent symptoms due to closure of the saphenous vein grafts, the development of atherosclerosis in the graft, or progression of underlying coronary disease. Interventions that reduce the failure of vein grafts would significantly benefit women following bypass surgery and possibly benefit all women with atherosclerotic disease. Observational studies in different populations of postmenopausal women suggest that postmenopausal estrogen replacement therapy reduces cardiac morbidity by 30-50%. However, a recently published, randomized, placebo-controlled clinical trial of Prempro in women with known coronary disease showed no overall difference in cardiovascular death or myocardial infarction after 4 years of study. Thus, the benefit of estrogen and progestin co-therapy (HRT) in women with established coronary disease has not been established. This study is a randomized, placebo-controlled trial using HRT started shortly after coronary bypass surgery to determine whether this treatment will delay the development of graft atherosclerosis and reduce the occurrence of graft occlusion. Women will be randomized to receive placebo or HRT with 17-beta estradiol plus medroxyprogesterone acetate for 3.5 years. The treatment will be started within 6 months of bypass surgery that involves placing a saphenous vein graft. The development of vein graft disease will be measured using quantitative coronary angiographic and intravascular ultrasound assessment of disease severity and extent performed at 6 months and compared to another assessment performed 3 years later. We shall determine the influence of HRT on the change in severity and extent of vein graft disease over 3.5 years of therapy. We postulate that the pathophysiologic mechanisms of platelet activation, fibrinogen binding to platelets, vascular reactivity, coagulation and fibrinolytic factors, and lipoprotein composition predict the occurrence of graft occlusion and graft atherosclerosis. The effect of HRT on these factors will be measured. The proposal also tests the hypothesis that HRT exerts its beneficial effects by its effects on these risk factors in addition to more traditional risk factors including lipids and lipoprotein profile. The influence of these risk factors and the effect of HRT on the frequency of early graft closure (identified on a 6-month coronary angiogram) will be assessed.